Impaired 11β-Hydroxysteroid Dehydrogenase Type 2 Activity in Kidney Disease Disrupts 11-Oxygenated Androgen Biosynthesis

Context: 11-Oxygenated androgens are a group of adrenal-derived steroids that require peripheral activation. In vitro data highlight a putative role for 11 beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) in 11-oxygenated androgen biosynthesis, converting 11(beta-hydroxyandrostenedione to 11-ketoandrostenedione (11KA4), the direct precursor of the potent androgen 11-ketotestosterone (11KT). As the kidney is the major site of HSD11B2 expression, we hypothesized that patients with chronic kidney disease (CKD) would have reduced 11-oxygenated androgen biosynthesis due to impaired HSD11B2 activity. Objective: To determine the role of HSD11B2 in 11-oxygenated androgen biosynthesis using a human CKD cohort alongside complementary cell culture and computational modeling approaches. Methods: Cross-sectional observational study of patients with CKD (n = 85) and healthy controls (n = 46) measuring serum and urinary concentrations of glucocorticoids, and classic and 11-oxygenated androgens by liquid chromatography tandem mass spectrometry. A computational model of peripheral 11-oxygenated androgen biosynthesis was fitted to the serum data to calculate relative HSD11B2 expression levels for each participant. Results: HSD11B2 activity declined with estimated glomerular filtration rate (eGFR), evidenced by higher cortisol/cortisone (E) ratios in patients with CKD than in controls (P < .0001). Serum concentrations of E, 11KA4, 11KT, and 11(beta-hydroxytestosterone were lower in patients with CKD than in controls (P < .0001 for each). A computational model based on enzyme kinetic parameters of HSD11B2, 11(beta-hydroxysteroid dehydrogenase type 1, 17(3-hydroxysteroid dehydrogenase type 2, and aldo-keto reductase 1C3 confirmed HSD11B2 as the key enzyme responsible for reduced 11-oxygenated androgen biosynthesis in CKD. Predicted HSD11B2 expression correlated with eGFR. Conclusion: This is the first in vivo study to confirm a central role for renal HSD11B2 in 11-oxygenated androgen biosynthesis. Determining the clinical implications of this observation for patients with CKD requires further research.